A. Background Regarding Cinacalcet
Cinacalcet hydrochloride is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. It is sold as Sensipar® in the USA and Australia, and Mimpara® in Europe. Its empirical formula is C22H22F3N.HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity (Sensipar® prescribing information; www.sensipar.com/professional/pdf/sensipar_pi.pdf, accessed Jun. 11, 2008). The structural formula of cinacalcet hydrochloride is shown below:

Cinacalcet HCl reduces iPTH, serum calcium, serum phosphorus, and the calcium-phosphorus product in patients with chronic kidney disease and secondary hyperparathyroidism who are receiving dialysis, and reduces elevated serum calcium associated with primary hyperparathyroidism and parathyroid carcinoma. Cinacalcet was approved in the US on 8 Mar. 2004 (NDA No. 021688) where it is sold under the tradename Sensipar® and in the European Union on 22 Oct. 2004 (MA EU/1/04/292/001-012) where it is sold as Mimpara®. Sensipar®/Mimpara® is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis. Sensipar® is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. In January 2008, Kirin Pharma (now Kyowa Hakko Kirin) launched cinacalcet, as Regpara™, for the treatment of secondary hyperparathyroidism. In June 2008, cinacalcet was approved in the EU for the treatment of hypercalcemia in primary hyperparathyroidism.
In patients with secondary hyperparathyroidism and end-stage renal disease on dialysis, cinacalcet is to be administered orally starting at 30 mg, once daily. The dose should be titrated every 2 to 4 weeks up to 180 mg daily, to achieve a target PTH level. For patients with parathyroid carcinoma the recommended starting oral dose of Sensipar® is 30 mg twice daily. This should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily and 90 mg three or four times daily as necessary to normalize serum calcium levels.
Cinacalcet is administered orally, and concomitant administration with food affects its bioavailability. Studies have confirmed this fact. Specifically, a study comparing the absorption of a single oral dose of cinacalcet HCl (Sensipar®/Mimpara® (90 mg) following (i) a high-fat, high-caloric meal, (ii) a low-fat, low-caloric meal, and a (iii) 10-hour fast, showed that the mean (90% confidence intervals) AUC[infinity] following high- and low-fat meals was increased by 68 (48 to 89) % and 50 (33 to 70) %, respectively, relative to fasting. The difference in mean AUC∞ between high- and low-fat meals was small [12 (9.9-26) %]. Moreover, the mean tmax of cinacalcet was prolonged in fasting subjects (6 h) in relation to high-fat (4 h) and low-fat (3.5 h) fed subjects. The mean t1/2[beta] was similar between treatment conditions. See American J. of Therapeutics, 14:235-240 (May/June 2007). Thus, administration of cinacalcet with either high- or low-fat meals results in significant increases in exposure, relative to administration under fasting conditions. This change in exposure requires that the medication be taken with food or shortly after a meal. If a patient does not take their dose exactly as indicated sub-therapeutic levels of cinacalcet can occur. A recommendation that cinacalcet to be taken with food or shortly after a meal is included in the labeling information issued by the FDA and EMEA in respect of the Sensipar® and Mimpara® products respectively (see FDA 2004 label information and EMEA 2004 Summary of Product Characteristics, available on the relevant agency's website). In the case of the US product the most recent revision of the label information (19 Dec. 2008) maintains this recommendation. The absolute bioavailability of cinacalcet in fasted subjects has been estimated at 20-25% (EMEA 2004 Summary of Product Characteristics for Mimpara®)
More generally, cinacalcet is used to treat hyperparathyroidism (elevated parathyroid hormone levels) Torres PU, “Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease”. Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation 16 (3): 253-8. (2006), and the symptoms thereof. Hyperparathyroidism is overactivity of the parathyroid glands resulting in excess production of parathyroid hormone (PTH). Parathyroid hormone regulates calcium and phosphate levels and helps to maintain these levels. Overactivity of one or more of the parathyroid glands causes high calcium levels (hypercalcemia) and low levels of phosphate in the blood. Hyperparathyroidism may be a consequence of parathyroid tumors and chronic renal failure.
Cinacalcet HCl is a white to off-white, crystalline solid soluble in methanol or 95% ethanol, but only slightly soluble in water. As such, the dissolution rate and bioavailability of known cinacalcet formulations are not optimal. The effectiveness of cinacalcet may be enhanced if it could be formulated to be taken without food, thus decreasing the likelihood of patient compliance problems. Furthermore a formulation that enhances the bioavailability of cinacalcet would facilitate reduction of the dosage strength with the possibility of achieving a better safety profile.
U.S. Pat. No. 6,011,068, U.S. Pat. No. 6,031,003, U.S. Pat. No. 6,211,244 and U.S. Pat. No. 6,313,146 are listed in respect of Sensipar® in the FDA's list of Approved Drug Products with Therapeutic Equivalence Evaluations (otherwise known as the “Orange Book”; see www.fda.gov/cder/ob/default.htm—accessed 5 May, 2009). Collectively these patents cover the cinacalcet compound per se, pharmaceutical compositions comprising cinacalcet and various uses including those listed in the Orange Book, namely: reducing parathyroid hormone level; modulating parathyroid hormone secretion; treating hyperparathyroidism; and reducing serum ionized calcium level.
B. Background Regarding Nanoparticulate Active Agent Compositions
Nanoparticulate active agent compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles comprising a poorly soluble therapeutic or diagnostic agent having adsorbed onto, or associated with, the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of cinacalcet.
Methods of making nanoparticulate active agent compositions are described in, for example, U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.” These do not describe nanoparticulate compositions of cinacalcet.
Nanoparticulate active agent compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form;” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” U.S. Pat. No. 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” U.S. Pat. No. 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract;” U.S. Pat. No. 6,592,903 for “Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” U.S. Pat. No. 6,582,285 for “Apparatus for sanitary wet milling;” U.S. Pat. No. 6,742,734 for “System and Method for Milling Materials;” U.S. Pat. No. 6,745,962 for “Small Scale Mill and Method Thereof;” U.S. Pat. No. 6,811,767 for “Liquid droplet aerosols of nanoparticulate drugs;” U.S. Pat. No. 6,908,626 for “Compositions having a combination of immediate release and controlled release characteristics;” U.S. Pat. No. 6,969,529 for “Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers;” U.S. Pat. No. 6,976,647 for “System and Method for Milling Materials;” U.S. Pat. No. 6,991,191 for “Method of Using a Small Scale Mill;” U.S. Pat. No. 7,198,795 for “In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions;” U.S. Pat. No. 7,244,451 for “Methods of making nanoparticulate drug compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers”; U.S. Pat. No. 7,288,267 for “Bioadhesive nanoparticulate compositions having cationic surface stabilizers”; U.S. Pat. No. 7,320,802 for “Methods of treatment using nanoparticulate fenofibrate compositions;” U.S. Pat. No. 7,390,505 for “Nanoparticulate topiramate formulations;” U.S. Pat. No. 7,459,283 for “Nanoparticulate compositions having lysozyme as a surface stabilizer;” U.S. Pat. No. 7,521,068 for “Dry powder aerosols of nanoparticulate drugs;” U.S. Pat. No. 7,695,739 for “In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate or nanoparticulate active agent compositions;” U.S. Pat. No. 7,713,551 for “Gel stabilized nanoparticulate active agent compositions;” U.S. Pat. No. 7,763,278 for “Nanoparticulate polycosanol formulations and novel polycosanol combinations;” U.S. Pat. No. RE41,884 for “Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions;” U.S. Pat. No. 7,825,087 for “Nanoparticulate and controlled release compositions comprising cyclosporine;” U.S. Pat. No. 7,842,232 for “Sterilization of dispersions of nanoparticulate active agents with gamma radiation;” U.S. Pat. No. 7,850,995 for “Bioadhesive nanoparticulate compositions having cationic surface stabilizers;” U.S. Pat. No. 7,879,360 for “Nanoparticulate compositions having a peptide as a surface stabilizer;” U.S. Pat. No. 7,910,577 for “Injectable nanoparticulate olanzapine formulations;” U.S. Pat. No. 7,927,627 for “Nanoparticulate fibrate formulations;” and U.S. Pat. No. 7,931,917 for “Nanoparticulate fibrate formulations,” all of which are specifically incorporated by reference. These patents do not describe nanoparticulate compositions of cinacalcet.
In addition, U.S. Patent Publication Nos. 20080152585 for “Low viscosity liquid dosage forms”; 20080124393 for “Controlled release nanoparticulate compositions”; 20080025807 for “System and Method for Milling Materials”; 20080003295 for “Bioadhesive nanoparticulate compositions having cationic surface stabilizers”; 20070141159 for “Methods of Making Nanoparticulate Compositions Comprising Copolymers of Vinyl Pyrrolidone and Vinyl Acetate as Surface Stabilizers”; 20070110776 for “In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate or nanoparticulate active agent compositions;” 20020012675 A1 for “Controlled Release Nanoparticulate Compositions,” 20040195413 A1, for “Compositions and method for milling materials,” 20040173696 A1 for “Milling microgram quantities of nanoparticulate candidate compounds,” 20020012675 A1 for “Controlled Release Nanoparticulate Compositions;” 20050238725 for “Nanoparticulate compositions having a peptide as a surface stabilizer;” 20050147664 for “Compositions comprising antibodies and methods of using the same for targeting nanoparticulate active agent delivery;” 20050031691 for “Gel stabilized nanoparticulate active agent compositions;” 20040258757 for “Liquid dosage compositions of stable nanoparticulate active agents;” 20040195413 for “Compositions and method for milling materials;” 20040156895 for “Solid dosage forms comprising pullulan;” 20040105889 for “Low viscosity liquid dosage forms;” 20040105778 for “Gamma irradiation of solid nanoparticulate active agents;” 20040015134 for “Drug delivery systems and methods;” 20030215502 for “Fast dissolving dosage forms having reduced friability;” 20030185869 for “Nanoparticulate compositions having lysozyme as a surface stabilizer;” 20030137067 for “Compositions having a combination of immediate release and controlled release characteristics;” 20030108616 for “Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers;” 20030087308 for “Method for high through put screening using a small scale mill or microfluidics;” 20030023203 for “Drug delivery systems & methods;” 20020179758 for “System and method for milling materials; 20010053664 for “Apparatus for sanitary wet milling,” 20110064803 for “Nanoparticulate and controlled release compositions comprising vitamin k2;” 20110027371 for “Nanoparticulate statin formulations and novel statin combinations;” 20110008435 for “Nanoparticulate and Controlled Release Compositions Comprising Aryl-Heterocyclic Compounds;” 20100316725 for “Reduction of flake-like aggregation in nanoparticulate active agent compositions;” 20100260859 “Controlled-release clozapine compositions;” 20100260858 for “Drug delivery composition;” 20100247636 for “Nanoparticulate and controlled release compositions comprising nilvadipine;” 20100221327 for “Nanoparticulate azelnidipine formulations;” 20100028439 for “Nanoparticulate stabilized anti-hypertensive compositions;” 20090304801 for “Aerosol and injectable formulations of nanoparticulate benzodiazepine;” 20090297596 for “Nanoparticulate and Controlled Release Compositions Comprising a Platelet Aggregation Inhibitor;” 20090291142 for “Nanoparticulate bicalutamide formulations;” 20090269400 for “Nanoparticulate and Controlled Release Compositions Comprising a Cephalosporin;” 20090252807 for “Nanoparticulate and Controlled Release Compositions Comprising Prostaglandin Derivatives;” 20090238884 for “Compositions for site-specific delivery of imatinib and methods of use;” 20090155331 for “Injectable nanoparticulate olanzapine formulations;” 20090074873 for “Nanoparticulate beclomethasone dipropionate compositions;” 20090035366 for “Nanoparticulate benzothiophene formulations;” 20080317843 for “Nanoparticulate formulations of modafinil;” 20080279929 for “Nanoparticulate and Controlled Release Compositions Comprising Cefditoren;” 20080254114 for “Controlled Release Compositions Comprising Heterocyclic Amide Derivative Nanoparticles;” 20080248123 for “Nanoparticulate anticonvulsant and immunosuppressive compositions;” 20080226734 for “Combination of a narcotic and non-narcotic analgesic;” 20080220074 for “Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same;” 20080213378 for “Nanoparticulate statin formulations and novel statin combinations;” 20080213374 for “Nanoparticulate sorafenib formulations;” and 20080171091 for “Nanoparticulate compositions of immunosuppressive agents,” describe nanoparticulate active agent compositions and are specifically incorporated by reference. These patent application publications do not describe nanoparticulate compositions of cinacalcet.
Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;”. These are also specifically incorporated herein by reference. These patents do not describe nanoparticulate compositions of cinacalcet.
The present invention relates to nanoparticulate cinacalcet compositions, such as nanoparticulate cinacalcet HCl, which addresses the needs described above by providing nanoparticulate cinacalcet compositions which overcome the shortcomings of known non-nanoparticulate cinacalcet formulations.